Throughout this application, patent and technical literature may be referred to by a Roman numeral, the full bibliographic citations for which are found immediately preceding the claims. This information as well as the documents identified in the specification are provided to more fully describe the state of the art to which this invention pertains. These disclosures are incorporated by reference into the specification.
Stereoselective reactions are essential for the pharmaceutical industry. Since 1988, the FDA has required that the enantiomeric composition of all drugs having stereocenters be known. Often times, the reactions used to establish chirality at one or more centers are not stereoselective or not as stereoselective as would be desired. This results in costly purification steps. It is contemplated that the use of the technique described herein could eliminate purification steps, limit the environmental impact associated with solvent usage in purification steps, and be general in its application to most stereoselective reactions.
The exclusion of organic solvents would be advantageous as most organic solvents are dangerous for a variety of reasons. For example, solvents can be flammable or highly flammable, depending on their volatility. Many solvents can lead to a sudden loss of consciousness if inhaled in large amounts. Methanol can cause internal damage to the eyes, including permanent blindness. The commonly used solvent, diethyl ether, has an exceptionally low autoignition temperature which greatly increases the fire risk associated with this solvent. In addition, commonly used ethers such as diethyl ether, tetrahydrofuran (THF) and diisopropyl ether, form highly explosive organic peroxides upon exposure to oxygen and light. When sufficient peroxides have formed, they can form a shock sensitive solid, and when this solid is formed at the mouth of the bottle, turning the cap may provide sufficient energy for the peroxide to detonate. In addition, if the solvent is concentrated after the completion of a reaction, detonation can occur without warning.
In addition to the dangerous laboratory hazards above, environmental and heath issues arise from spills or leaks of solvents that reach the underlying soil. Since solvents readily migrate substantial distances, the creation of widespread soil contamination is not uncommon; there may be about 5000 sites worldwide that have major subsurface solvent contamination; this is particularly a health risk if aquifers are affected. Some solvents including chloroform and benzene are carcinogenic, and many others can damage internal organs like the liver, the kidneys, or the brain.
Disclosed herein are methods for alleviating the need for solvents in asymmetric reactions. Such methods rely on the utilization of ultrasonic irradiation. Currently, the overwhelming majority of reports detailing the effects of ultrasonic irradiation upon chemistry are concerned with heterogeneous reactions. In these studies, ultrasound has been applied simply as a means to increase the area of contact between reactants or a reactant and catalyst.i-iii To our knowledge, only three successful uses of ultrasound in homogeneous chemistry exist.iv-vii H. C. Brown has shown an increased yield in the hydroboration of alkenes using a number of organoboranes were increased to nearly quantitative amounts while reaction times were shortened considerably under ultrasonic irradiation.vi 
The principal conclusion from preliminary work of the Suslick group at the University of Illinois, Urbana-Champaign performed in the 1980s is that cavitation is responsible for many of the phenomena observed in sonochemistry.viii Cavitations are derived from the nucleation of bubbles at weak spots in liquid structure and the subsequent collapse of these low density regions. The collapse of the bubble is thought to generate what are known as ‘hot spots’. High local pressures and temperatures are thought to be associated with these ‘hot spots’. Local temperatures on the order of 5000 K are thought to be generated in the immediate vicinity of cavitations.ix Estimates of pressures range from 1-10 Kbar.x Recently, pressure broadening studies upon sonoluminescing bubbles have estimated intracavity pressures have been measured between 1.6 and 3.7 Kbar.xi 
The Evans-Polanyi equation illustrates how pressure affects rate (equation 1). For most bimolecular reactions, the volume of activation (ΔV≠) is negative, which translates into a rate enhancement upon the application of pressure.xii,xiii (∂ ln k/∂P)T=−ΔV≠/RT  (1)
If two competing pathways are operative in a reaction, such as endo/exo competition in Diels-Alder reactions, antil syn competition in aldol reactions, and Rel Si competition in stereoselective reductions, then the pathway with the largest negative volume of activation (smallest transition state volume) will be accelerated to a greater degree than the pathway with the smaller negative volume of activation (larger transition state volume).xiv,xv Stereochemical outcomes are often thought to be dominated by steric interactions. This principle is demonstrated in the Felkin-Anh modelxvi and has been quantitatively shown in the DIP-Cl reduction of prochiral ketones.xvii For different reasons (secondary orbital overlap), the endo transition state in the Diels-Alder reaction is often preferred over the exo transition state. However, in the hetero-Diels-Alder reaction, the exo-product is preferred. This is perhaps due to overwhelming steric occlusion that occurs in the endo-transition structure as a result of substitution of the diene. Such a model makes sense, given that the application of high static pressures drastically increase diastereoselectivity.xviii The reversal in stereoselectivity observed in the Mukaiyama aldol reaction has been rationalized by the pressure-induced preference for a more compact boat-like transition structure over the typical Zimmerman transition structure.xix The results reported herein are consonant with reports that the application of high static pressures (6000 Kbar) drastically improve stereoselection in Alpine Borane reductions.
In order to decrease both the heath and environmental risks associated with the use of organic solvents, chemists must come up with alternative methods for organic synthesis. Any alternative methods may either improve or maintain the yield or selectivity of a reaction which utilizes significant amounts of organic solvents. The use of solvent-free methods would greatly decrease these risks and allow for environmentally friendly or “green” chemistry.